Integrins and other cell surface receptors for extracellular matrix proteins such as fibronectin function in embryonic development and wound healing. Previous studies demonstrated key roles for integrins in early development. Our recent findings suggest novel potential roles in tooth development and wound repair, and they provide insights into integrin mechanisms of action. In tooth development, we found rapid changes in beta5 integrin mRNA expression and unusually prominent expression of the alpha-v integrin. Differences between the expression patterns of beta3 and beta5 integrin subunits in embryos versus alpha-v and beta1 subunits correlated with their different integrin partner specificities: the latter two pair with many other subunits, while the former are specific. Studies on keratinocytes showed that the distribution pattern of integrins depended on the type of adhesive structure. A collaborative study of periodontal disease tissue revealed disruption of the organization of beta1 integrins and extracellular proteins. Studies of integrin mechanisms of action focused on their binding to target ligands such as fibronectin and subsequent responses. Although binding of the human fibronectin receptor alpha5beta1 generally requires a two-site mechanism involving a synergy site, maximal activation of this integrin allows it to bypass this requirement, suggesting a novel regulatory mechanism. The roles of integrin ligand occupancy, aggregation, and a combination of these two events are being tested using natural ligands, peptides, and monoclonal antibodies. Distinct roles were identified for occupancy versus aggregation, as well as synergistic effects of the combination in controlling receptor location, signaling, and association with different classes of cytoskeletal molecules. These approaches provide novel tools for understanding how extracellular molecules regulate cellular functions. Because alterations in integrin function may contribute to a variety of human congenital defects and affect wound healing, these studies also provide an opportunity to identify new pathways as targets for potential therapy.